Myeloid cells are key regulators of tissue homeostasis and disease. Alterations in cell-autonomous
insulin/IGF-1 signaling in myeloid cells have recently been implicated in the development of systemic
inflammation and
insulin-resistant
diabetes mellitus type 2 (DM). Impaired wound healing and inflammatory
skin diseases are frequent DM-associated skin pathologies, yet the underlying mechanisms are elusive. In this study, we investigated whether myeloid cell-restricted IR/IGF-1R signaling provides a pathophysiologic link between systemic
insulin resistance and the development of cutaneous
inflammation. Therefore, we generated mice lacking both the
insulin and
IGF-1 receptor in myeloid cells (IR/IGF-1R(MKO)). Whereas the kinetics of
wound closure following acute skin injury was similar in control and IR/IGF-1R(MKO) mice, in two different conditions of
dermatitis either induced by repetitive topical applications of the
detergent SDS or by high-dose UV B radiation, IR/IGF-1R(MKO) mice were protected from
inflammation, whereas controls developed severe skin
dermatitis. Notably, whereas during the early phase in both inflammatory conditions the induction of epidermal proinflammatory
cytokine expression was similar in control and IR/IGF-1R(MKO) mice, during the late stage, epidermal
cytokine expression was sustained in controls but virtually abrogated in IR/IGF-1R(MKO) mice. This distinct kinetic of epidermal
cytokine expression was paralleled by proinflammatory macrophage activation in controls and a noninflammatory phenotype in mutants. Collectively, our findings provide evidence for a proinflammatory IR/IGF-1R-dependent pathway in myeloid cells that plays a critical role in the dynamics of an epidermal-dermal cross-talk in cutaneous inflammatory responses, and may add to the mechanistic understanding of diseases associated with disturbances in myeloid cell IR/IGF-1R signaling, including DM.